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    Clinical Trial Results:
    A Randomized Phase 3, Multicenter, Open-Label Study Comparing TH-302 in Combination with Doxorubicin vs. Doxorubicin Alone in Subjects with Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma.

    Summary
    EudraCT number
    		 2011-003145-17
    Trial protocol
    		 ES   DE   HU   PL   BE   IT   AT   DK  
    Global end of trial date
    19 Oct 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Dec 2017
    First version publication date
    08 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TH-CR-406/SARC021
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01440088
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Molecular Templates
    Sponsor organisation address
    9301 Amberglen Blvd, Suite 100, Austin, United States, TX 78729
    Public contact
    David J. Valacer, MD Chief Medical Officer, Molecular Templates, 201 961-4477, david.valacer@mtem.com
    Scientific contact
    David J. Valacer, MD Chief Medical Officer, Molecular Templates, 201 961-4477, david.valacer@mtem.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Oct 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Oct 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. To evaluate the efficacy of TH-302 in combination with doxorubicin as determined by overall survival (OS) in subjects with locally advanced unresectable or metastatic soft tissue sarcoma previously untreated with chemotherapy (neoadjuvant and adjuvant chemotherapy permitted) compared with doxorubicin alone. 2. To assess the safety of TH-302 in combination with doxorubicin in subjects with locally advanced unresectable or metastatic soft tissue sarcoma compared with doxorubicin alone.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and with all appropriate national and local regulations and guidances, including United States (US) Code of Federal Regulations (CFRs) on Good Clinical Practices (GCP) and the International Conference on Harmonisation (ICH) guideline E6: Good Clinical Practices. All subjects eligible for screening signed the consent prior to the performance of any non-routine procedures. Before undertaking any study-related procedure, the investigators or their designees explained the nature and purpose of the study, participation and termination conditions, and risks and benefits to the subject.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Sep 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Poland: 14
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 27
    Country: Number of subjects enrolled
    Denmark: 14
    Country: Number of subjects enrolled
    France: 38
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    Hungary: 39
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    Canada: 23
    Country: Number of subjects enrolled
    Russian Federation: 16
    Country: Number of subjects enrolled
    United States: 383
    Worldwide total number of subjects
    640
    EEA total number of subjects
    211
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    431
    From 65 to 84 years
    209
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study had planned to enroll 620 subjects, however, 640 subjects were enrolled in a 1:1 ratio (317 in TH-302 + doxorubicin arm and 323 in doxorubicin alone arm). Nineteen subjects did not receive treatment and thus, 621 subjects received the study drug (313 to the TH-302 plus doxorubicin arm and 308 to the doxorubicin alone arm).

    Pre-assignment
    Screening details
    		 Screening took place within 3 weeks prior to Cycle 1 Day 1.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Doxorubicin
    Arm description
    		 Subjects received doxorubicin (75 mg/m2) either by bolus injection (no less than 5 minutes) or by continuous intravenous (IV) infusion over 6-96 hours on Day 1 of every 21-day cycle; doxorubicin was not administered after 6 cycles of treatment. Doxorubicin administration was to start between 2 to 4 hours after completion of the TH-302 infusion when used in combination with TH-302
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion, Injection
    Routes of administration
    Intravenous bolus use , Intravenous drip use
    Dosage and administration details
    Subjects received doxorubicin (75 mg/m2) either by bolus injection (no less than 5 minutes) or by continuous IV infusion over 6-96 hours on Day 1 of every 21-day cycle; doxorubicin was not administered after 6 cycles of treatment.

    Arm title
    		 TH-302 + Doxorubicin
    Arm description
    		 Subjects received TH-302 (300 mg/m2) by IV infusion over 30-60 minutes on Days 1 and 8 of a 21-day cycle and doxorubicin (75 mg/m2) either by bolus injection (no less than 5 minutes) or by continuous intravenous (IV) infusion over 6-96 hours on Day 1 of every 21-day cycle 2 started 2 to 4 hours after completion of TH-302 administration.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TH-302 + Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Subjects received TH-302 (300 mg/m2) by IV infusion over 30-60 minutes on Days 1 and 8 of a 21-day cycle and doxorubicin (75 mg/m2) either by bolus injection (no less than 5 minutes) or by continuous intravenous (IV) infusion over 6-96 hours on Day 1 of every 21-day cycle 2 started 2 to 4 hours after completion of TH-302 administration.

    Number of subjects in period 1
    		Doxorubicin TH-302 + Doxorubicin
    Started
    323
    317
    Completed
    170
    160
    Not completed
    153
    157
         Ongoing
    -
    9
         Early Termination
    153
    148

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Doxorubicin
    Reporting group description
    		 Subjects received doxorubicin (75 mg/m2) either by bolus injection (no less than 5 minutes) or by continuous intravenous (IV) infusion over 6-96 hours on Day 1 of every 21-day cycle; doxorubicin was not administered after 6 cycles of treatment. Doxorubicin administration was to start between 2 to 4 hours after completion of the TH-302 infusion when used in combination with TH-302

    Reporting group title
    TH-302 + Doxorubicin
    Reporting group description
    		 Subjects received TH-302 (300 mg/m2) by IV infusion over 30-60 minutes on Days 1 and 8 of a 21-day cycle and doxorubicin (75 mg/m2) either by bolus injection (no less than 5 minutes) or by continuous intravenous (IV) infusion over 6-96 hours on Day 1 of every 21-day cycle 2 started 2 to 4 hours after completion of TH-302 administration.

    Reporting group values
    		 Doxorubicin TH-302 + Doxorubicin Total
    Number of subjects
    		 323 317 640
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 220 211 431
        From 65-84 years
    		 103 106 209
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.7 ( 13.07 ) 57.4 ( 12.83 ) -
    Gender categorical
    Units: Subjects
        Female
    		 172 173 345
        Male
    		 151 144 295

    End points

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    End points reporting groups
    Reporting group title
    Doxorubicin
    Reporting group description
    		 Subjects received doxorubicin (75 mg/m2) either by bolus injection (no less than 5 minutes) or by continuous intravenous (IV) infusion over 6-96 hours on Day 1 of every 21-day cycle; doxorubicin was not administered after 6 cycles of treatment. Doxorubicin administration was to start between 2 to 4 hours after completion of the TH-302 infusion when used in combination with TH-302

    Reporting group title
    TH-302 + Doxorubicin
    Reporting group description
    		 Subjects received TH-302 (300 mg/m2) by IV infusion over 30-60 minutes on Days 1 and 8 of a 21-day cycle and doxorubicin (75 mg/m2) either by bolus injection (no less than 5 minutes) or by continuous intravenous (IV) infusion over 6-96 hours on Day 1 of every 21-day cycle 2 started 2 to 4 hours after completion of TH-302 administration.

    Primary: Overal survivial (OS)

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    End point title
    		 Overal survivial (OS)
    End point description
    Overall survival was defined as the duration from date of randomization to date of death by any cause. All randomized subjects (intent-to-treat (ITT) population) were included for the analysis. The analysis was performed when 423 deaths were reported. Overall survival was measured from the date of randomization to death from any cause.
    End point type
    Primary
    End point timeframe
    Every 3 months until up to 3 years from study entry until death/lost to follow-up/study closure. After discontinuation of study treatment without progressive disease: Every 9 weeks for first 18 weeks & then every 9 to 15 weeks thereafter/more frequently.
    End point values
    		 Doxorubicin TH-302 + Doxorubicin
    Number of subjects analysed
    323
    317
    Units: Days
    median (confidence interval 95%)
        OS (Median value)
    578 (493 to 681)
    561 (475 to 672)
        OS rates at 6 months (Point Estimate)
    83 (78 to 87)
    85 (81 to 89)
        OS rates at 12 months (Point Estimate)
    65 (60 to 70)
    65 (59 to 70)
        OS rates at 18 months (Point Estimate)
    53 (47 to 58)
    50 (45 to 56)
        OS rates at 24 months (Point Estimate)
    43 (37 to 48)
    40 (35 to 46)
        OS rates at 36 months (Point Estimate)
    29 (23 to 35)
    19 (12 to 28)
    Statistical analysis title
    		 Overall survival
    Statistical analysis description
    Kaplan-Meier formula was used to estimate survival. Estimates and confidence intervals were calculated by the product limit method and Greenwood's formula for the variance. A two-sided log-rank test stratified by randomization stratification factors was used to test the significance between the two treatment arms.
    Comparison groups
    Doxorubicin v TH-302 + Doxorubicin
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.5267
    Method
    		 Two-sided log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.878
         upper limit
    		 1.289
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.064

    Primary: Safety of TH-302 in combination with doxorubicin compared with doxorubicin alone by assessment of the number of adverse events

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    End point title
    		 Safety of TH-302 in combination with doxorubicin compared with doxorubicin alone by assessment of the number of adverse events [1]
    End point description
    To assess the safety of TH-302 in combination of doxorubicin in subjects with locally advanced unresectable or metastatic STS compared with doxorubicin alone
    End point type
    Primary
    End point timeframe
    From the first administration of study drug until 30 days after the last dose of study drug.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Primary endpoint was safety, which was presented descriptively and extensively in the posted results.
    End point values
    		 Doxorubicin TH-302 + Doxorubicin
    Number of subjects analysed
    323
    317
    Units: Number
        All AEs
    307
    312
        AEs Related to TH-302
    0
    301
        AEs Related to Doxorubicin
    292
    304
        All Grade ≥ 3 AEs
    231
    246
        Grade ≥ 3 AEs Related to TH-302
    0
    208
        Grade ≥ 3 AEs Related to Doxorubicin
    200
    209
        AEs lead to TH-302 reduciton & interruption
    0
    197
        AEs lead to doxorubicin reduciton & interruption
    102
    138
        AEs lead to discontinuation of TH-302
    0
    41
        AEs lead to discontinuation of doxorubicin
    19
    26
        All SAEs
    99
    145
        SAEs Related to TH-302
    0
    96
        SAEs Related to doxorubicin
    58
    100
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS)
    End point description
    Progression-free survival (PFS) was defined as time from randomization to the first occurrence of PD or death from any cause within 63 days of last response assessment or randomization. PFS consisted of all randomized subjects (ITT population) for the analysis. To evaluate the efficacy of TH-302 in combination with doxorubicin as determined by PFS in subjects with locally advanced unresectable or metastatic STS compared with doxorubicin alone.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to the first occurrence of progressive disease (PD) or death from any cause up to 63 days following last response assessment (or from start of treatment for subjects without a response assessment), whichever occurred first
    End point values
    		 Doxorubicin TH-302 + Doxorubicin
    Number of subjects analysed
    323
    317
    Units: Days
    median (confidence interval 95%)
        PFS (Median value)
    182 (140 to 190)
    191 (183 to 237)
        PFS rates at 6 Months survival (Point
    49 (42 to 55)
    56 (50 to 61)
        PFS rates at 12 Months survival (Point
    16 (10 to 22)
    25 (20 to 31)
        PFS rates at 18 Months survival (Point
    11 (7 to 17)
    15 (11 to 20)
        PFS rates at 24 Months survival (Point
    8 (4 to 14)
    9 (5 to 14)
        PFS rates at 36 Months survival (Point
    8 (4 to 14)
    7 (4 to 13)
    Statistical analysis title
    		 Progression-free survival (PFS)
    Statistical analysis description
    Resection were censored for analysis related to response evaluation criteria in solid tumors (RECIST) response assessment at the time of the last response assessment prior to resection. A two-sided log-rank test stratified by randomization stratification factors was used to test the significance between the two treatment arms.
    Comparison groups
    Doxorubicin v TH-302 + Doxorubicin
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0986
    Method
    		 Two-sided stratified log rank test
    Parameter type
    		 Hazard ratio
    Point estimate
    0.849
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.698
         upper limit
    		 1.031

    Secondary: Tumor response - Best response

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    End point title
    		 Tumor response - Best response
    End point description
    A subject was identified as having a response, if they had a partial response (PR) or complete response (CR) on at least one tumor assessment. A subject was identified as having a best response of at least stable disease (SD), if they had an SD, PR or CR on at least one tumor assessment. The SD response must have occurred at least 5 weeks (> 35 days) after the initial dose.
    End point type
    Secondary
    End point timeframe
    At screening, end of Cycles 2, 4 & 6 (at every 3rd cycle for subjects continuing to Cycle 7 to Cycle 12 & every 3rd to 5th cycle thereafter), termination & every 9 weeks post treatment for 1st 18 weeks; every 9 to 15 weeks thereafter after discontinuation
    End point values
    		 Doxorubicin TH-302 + Doxorubicin
    Number of subjects analysed
    323
    317
    Units: Number
        Complete response
    3
    5
        Partial response
    56
    85
        Stable disease
    154
    142
        Progressive disease
    81
    64
        Unable to evaluate
    1
    1
        no resposne assessment on study
    28
    20
    Statistical analysis title
    		 Complete Response
    Comparison groups
    Doxorubicin v TH-302 + Doxorubicin
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.4541
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 95% Binomial confidence interval
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 2.4
    Statistical analysis title
    		 Partial Response or Better
    Comparison groups
    Doxorubicin v TH-302 + Doxorubicin
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0026
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 95% Binomial confidence interval
    Point estimate
    23.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 20.1
         upper limit
    		 26.8
    Statistical analysis title
    		 Stable Disease or Better Response
    Comparison groups
    Doxorubicin v TH-302 + Doxorubicin
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 95% Binomial confidence interval
    Point estimate
    69.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 65.8
         upper limit
    		 73.1

    Secondary: Tumor response - Confirmed repsosne

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    End point title
    		 Tumor response - Confirmed repsosne
    End point description
    A subjects was identified as having a response, if they had a partial response (PR) or complete response (CR) on at least one tumor assessment. A subject was identified as having a best response of at least stable disease (SD), if they had an SD, PR or CR on at least one tumor assessment. The SD response must have occurred at least 5 weeks (> 35 days) after the initial dose
    End point type
    Secondary
    End point timeframe
    At screening, end of Cycles 2, 4 & 6 (at every 3rd cycle for subjects continuing to Cycle 7 to Cycle 12 & every 3rd to 5th cycle thereafter), termination & every 9 weeks post treatment for 1st 18 weeks; every 9 to 15 weeks thereafter after discontinuation
    End point values
    		 Doxorubicin TH-302 + Doxorubicin
    Number of subjects analysed
    323
    317
    Units: Number
        Complete repsosne
    3
    3
        Partial resposne
    43
    67
        Stable disease
    167
    162
        Progressive disease
    81
    64
        No repsosne assessment on study
    29
    21
    Statistical analysis title
    		 Confirmed Complete Response
    Comparison groups
    Doxorubicin v TH-302 + Doxorubicin
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.9908
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 95% Binomial confidence interval
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 2
    Statistical analysis title
    		 Confirmed Partial Response or Better
    Comparison groups
    Doxorubicin v TH-302 + Doxorubicin
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0115
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 95% Binomial confidence interval
    Point estimate
    18.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 15.2
         upper limit
    		 21.3

    Secondary: Assessment of time to maximum concentration (Tmax) for TH-302, bromo-isophosphoramide mustard (Br-IPM), doxorubicin and doxorubicinol in plasma

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    End point title
    		 Assessment of time to maximum concentration (Tmax) for TH-302, bromo-isophosphoramide mustard (Br-IPM), doxorubicin and doxorubicinol in plasma
    End point description
    To assess the time to maximum concentration for TH-302, Br-IPM, doxorubicin and doxorubicinol after the IV administration of TH-302 and doxorubicin.
    End point type
    Secondary
    End point timeframe
    For TH-302 and Br-IPM: On Day 1 of Cycle 1 for subjects who received TH-302. For doxorubicin: On Day 1 of Cycle 1
    End point values
    		 Doxorubicin TH-302 + Doxorubicin
    Number of subjects analysed
    323 [2]
    317 [3]
    Units: Hour
    geometric mean (standard deviation)
        TH-302 (Participant count = 257)
    0 ( 0 )
    0.86 ( 1.361 )
        Br-IPM (Participant count = 199)
    0 ( 0 )
    0.9 ( 1.356 )
        Doxorubicin (Participant count = 24)
    0.37 ( 1.758 )
    0 ( 0 )
        Doxorubicin (Participant count = 22)
    0 ( 0 )
    0.32 ( 1.649 )
        Doxorubicinol (Participant count = 25)
    0.92 ( 2.615 )
    0 ( 0 )
        Doxorubicinol (Participant count = 23)
    0 ( 0 )
    0.85 ( 2.303 )
    Notes
    [2] - Doxorubicin (Participant count = 24) Doxorubicinol (Participant count = 25)
    [3] - Doxorubicin (Participant count = 22) Doxorubicinol (Participant count = 23)
    No statistical analyses for this end point

    Secondary: Assessment of Maximum peak observed concentration (Cmax) for TH-302, Br-IPM, doxorubicin and doxorubicinol in plasma

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    End point title
    		 Assessment of Maximum peak observed concentration (Cmax) for TH-302, Br-IPM, doxorubicin and doxorubicinol in plasma
    End point description
    To assess the maximum peak observed concentration (Cmax) for TH-302, Br-IPM, doxorubicin and doxorubicinol after the IV administration of TH-302 and doxorubicin.
    End point type
    Secondary
    End point timeframe
    For TH-302 and Br-IPM: On Day 1 of Cycle 1 for subjects who received TH-302. For doxorubicin: On Day 1 of Cycle 1
    End point values
    		 Doxorubicin TH-302 + Doxorubicin
    Number of subjects analysed
    323 [4]
    317 [5]
    Units: μg/mL
    geometric mean (standard deviation)
        TH-302 (Participant count = 257)
    0 ( 0 )
    4.69 ( 1.57 )
        Br-IPM (Participant count = 226)
    0 ( 0 )
    0.08 ( 1.601 )
        Doxorubicin (Participant count = 26)
    2.03 ( 1.871 )
    0 ( 0 )
        Doxorubicin (Participant count = 25)
    0 ( 0 )
    2.08 ( 2.197 )
        Doxorubicinol (Participant count = 26)
    0.05 ( 1.543 )
    0 ( 0 )
        Doxorubicinol (Participant count = 25)
    0 ( 0 )
    0.04 ( 1.677 )
    Notes
    [4] - Doxorubicin (Participant count = 26) Doxorubicinol (Participant count = 26)
    [5] - Doxorubicin (Participant count = 25) Doxorubicinol (Participant count = 25)
    No statistical analyses for this end point

    Secondary: Assessment of the magnitude of the slope of the linear regression of the log concentration versus time profile during the terminal phase (Kel (LAMZ)) for TH-302, Br-IPM and doxorubicin in plasma

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    End point title
    		 Assessment of the magnitude of the slope of the linear regression of the log concentration versus time profile during the terminal phase (Kel (LAMZ)) for TH-302, Br-IPM and doxorubicin in plasma
    End point description
    To assess the magnitude of the slope of the linear regression of the log concentration versus time profile during the terminal phase (Kel (LAMZ)) for TH-302, Br-IPM and doxorubicin after the IV administration of TH-302 and doxorubicin.
    End point type
    Secondary
    End point timeframe
    For TH-302 and Br-IPM: On Day 1 of Cycle 1 for subjects who received TH-302. For doxorubicin: On Day 1 of Cycle 1
    End point values
    		 Doxorubicin TH-302 + Doxorubicin
    Number of subjects analysed
    323 [6]
    317 [7]
    Units: Hour-1
    geometric mean (standard deviation)
        TH-302 (Participant count = 215)
    0 ( 0 )
    1.24 ( 1.198 )
        Br-IPM (Participant count = 1)
    0 ( 0 )
    0.73 ( 0 )
        Doxorubicin (Participant count = 10)
    0.06 ( 1.224 )
    0 ( 0 )
        Doxorubicin (Participant count = 13)
    0 ( 0 )
    0.06 ( 1.243 )
    Notes
    [6] - Doxorubicin (Participant count = 10)
    [7] - Doxorubicin (Participant count = 13)
    No statistical analyses for this end point

    Secondary: Assessment of half-life computed as in(2)/Kel (T1/2) for TH-302, Br-IPM and doxorubicin in plasma

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    End point title
    		 Assessment of half-life computed as in(2)/Kel (T1/2) for TH-302, Br-IPM and doxorubicin in plasma
    End point description
    To assess the half-life computed as in(2)/Kel (T1/2) for TH-302, Br-IPM and doxorubicin after the IV administration of TH-302 and doxorubicin.
    End point type
    Secondary
    End point timeframe
    For TH-302 and Br-IPM: On Day 1 of Cycle 1 for subjects who received TH-302. For doxorubicin: On Day 1 of Cycle 1
    End point values
    		 Doxorubicin TH-302 + Doxorubicin
    Number of subjects analysed
    323 [8]
    317 [9]
    Units: Hour
    geometric mean (standard deviation)
        TH-302 (Participant count = 215)
    0 ( 0 )
    0.56 ( 1.198 )
        Br-IPM (Participant count = 1)
    0 ( 0 )
    0.95 ( 0 )
        Doxorubicin (Participant count = 10)
    12.33 ( 1.225 )
    0 ( 0 )
        Doxorubicin (Participant count = 13)
    0 ( 0 )
    12.24 ( 1.243 )
    Notes
    [8] - Doxorubicin (Participant count = 10)
    [9] - Doxorubicin (Participant count = 13)
    No statistical analyses for this end point

    Secondary: Assessment of area under the concentration-time curve from hour 0 through the last quantifiable concentration time (AUClast) for TH-302, Br-IPM, doxorubicin and doxorubicinol in plasma

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    End point title
    		 Assessment of area under the concentration-time curve from hour 0 through the last quantifiable concentration time (AUClast) for TH-302, Br-IPM, doxorubicin and doxorubicinol in plasma
    End point description
    To assess area under the concentration-time curve from hour 0 through the last quantifiable concentration time (AUClast) for TH-302, Br-IPM, doxorubicin and doxorubicinol after the IV administration of TH-302 and doxorubicin.
    End point type
    Secondary
    End point timeframe
    For TH-302 and Br-IPM: On Day 1 of Cycle 1 for subjects who received TH-302. For doxorubicin: On Day 1 of Cycle 1
    End point values
    		 Doxorubicin TH-302 + Doxorubicin
    Number of subjects analysed
    323 [10]
    317 [11]
    Units: μg-h/mL
    geometric mean (standard deviation)
        TH-302 (Participant count = 257)
    0 ( 0 )
    4.56 ( 1.522 )
        Br-IPM (Participant count = 224)
    0 ( 0 )
    0.06 ( 2.05 )
        Doxorubicin (Participant count = 24)
    1.64 ( 1.326 )
    0 ( 0 )
        Doxorubicin (Participant count = 22)
    0 ( 0 )
    1.54 ( 1.308 )
        Doxorubicinol (Participant count = 25)
    0.57 ( 1.514 )
    0 ( 0 )
        Doxorubicinol (Participant count = 23)
    0 ( 0 )
    0.46 ( 1.738 )
    Notes
    [10] - Doxorubicin (Participant count = 24) Doxorubicinol (Participant count = 25)
    [11] - Doxorubicin (Participant count = 22) Doxorubicinol (Participant count = 23)
    No statistical analyses for this end point

    Secondary: Assessment of area under the concentration-time curve from 0 to infinity, computed using the linear trapezoidal rule as AUClast + CLCLQCT/ Kel (AUC 0-∞) for TH-302, Br-IPM and doxorubicin in plasma

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    End point title
    		 Assessment of area under the concentration-time curve from 0 to infinity, computed using the linear trapezoidal rule as AUClast + CLCLQCT/ Kel (AUC 0-∞) for TH-302, Br-IPM and doxorubicin in plasma
    End point description
    To assess area under the concentration-time curve from 0 to infinity, computed using the linear trapezoidal rule as AUClast + CLCLQCT/ Kel (AUC 0-∞) for TH-302, Br-IPM and doxorubicin after the IV administration of TH-302 and doxorubicin.
    End point type
    Secondary
    End point timeframe
    For TH-302 and Br-IPM: On Day 1 of Cycle 1 for subjects who received TH-302. For doxorubicin: On Day 1 of Cycle 1
    End point values
    		 Doxorubicin TH-302 + Doxorubicin
    Number of subjects analysed
    323 [12]
    317 [13]
    Units: μg-h/mL
    geometric mean (standard deviation)
        TH-302 (Participant count = 215)
    0 ( 0 )
    4.87 ( 1.504 )
        Br-IPM (Participant count = 1)
    0 ( 0 )
    0.29 ( 0 )
        Doxorubicin (Participant count = 10)
    2.03 ( 1.261 )
    0 ( 0 )
        Doxorubicin (Participant count = 13)
    0 ( 0 )
    1.75 ( 1.36 )
    Notes
    [12] - Doxorubicin (Participant count = 10)
    [13] - Doxorubicin (Participant count = 13)
    No statistical analyses for this end point

    Secondary: Assessment of clearance computed as dose divided by AUC0-∞ (CL) for TH-302 and doxorubicin in plasma

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    End point title
    		 Assessment of clearance computed as dose divided by AUC0-∞ (CL) for TH-302 and doxorubicin in plasma
    End point description
    To assess the time to maximum concentration for TH-302, Br-IPM and doxorubicin after the IV administration of TH-302 and doxorubicin.
    End point type
    Secondary
    End point timeframe
    For TH-302 and Br-IPM: On Day 1 of Cycle 1 for subjects who received TH-302. For doxorubicin: On Day 1 of Cycle 1
    End point values
    		 Doxorubicin TH-302 + Doxorubicin
    Number of subjects analysed
    323 [14]
    317 [15]
    Units: L/h/m2
    geometric mean (standard deviation)
        TH-302 (Participant count = 215)
    0 ( 0 )
    61.62 ( 1.504 )
        Doxorubicin (Participant count = 10)
    36.96 ( 1.261 )
    0 ( 0 )
        Doxorubicin (Participant count = 13)
    0 ( 0 )
    41.96 ( 1.327 )
    Notes
    [14] - Doxorubicin (Participant count = 10)
    [15] - Doxorubicin (Participant count = 13)
    No statistical analyses for this end point

    Secondary: Assessment of Apparent steady-state volume of distribution (Vss) for TH-302 and doxorubicin in plasma

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    End point title
    		 Assessment of Apparent steady-state volume of distribution (Vss) for TH-302 and doxorubicin in plasma
    End point description
    To assess the time to maximum concentration for TH-302, Br-IPM and doxorubicin after the IV administration of TH-302 and doxorubicin.
    End point type
    Secondary
    End point timeframe
    TH-302 & Br-IPM: On Day 1 of Cycle 1 for subjects who received TH-302. Doxorubicin: On Day 1 of Cycle 1; computed as Dose*AUMC/AUC0-∞ 2 - Dose*T/(2*AUC0-∞), where AUMC- area under the first moment of plasma concentration time curve & T- infusion duration
    End point values
    		 Doxorubicin TH-302 + Doxorubicin
    Number of subjects analysed
    323 [16]
    317 [17]
    Units: L/m2
    geometric mean (standard deviation)
        TH-302 (Participant count = 215)
    0 ( 0 )
    54.9 ( 1.521 )
        Doxorubicin (Participant count = 10)
    377.36 ( 1.455 )
    0 ( 0 )
        Doxorubicin (Participant count = 13)
    0 ( 0 )
    401.07 ( 1.378 )
    Notes
    [16] - Doxorubicin (Participant count = 10)
    [17] - Doxorubicin (Participant count = 13)
    No statistical analyses for this end point

    Secondary: Assessment of apparent volume of distribution in the post-distributive phase (Vβ) for TH-302 and doxorubicin in plasma

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    End point title
    		 Assessment of apparent volume of distribution in the post-distributive phase (Vβ) for TH-302 and doxorubicin in plasma
    End point description
    To assess the apparent volume of distribution in the post-distributive phase, computed as the ratio of CL to the terminal elimination rate constant, Kel (TH-302 and doxorubicin only)
    End point type
    Secondary
    End point timeframe
    For TH-302 and Br-IPM: On Day 1 of Cycle 1 for subjects who received TH-302. For doxorubicin: On Day 1 of Cycle 1
    End point values
    		 Doxorubicin TH-302 + Doxorubicin
    Number of subjects analysed
    323 [18]
    317 [19]
    Units: L/m2
    geometric mean (standard deviation)
        TH-302 (Participant count = 215)
    0 ( 0 )
    49.61 ( 1.508 )
        Doxorubicin (Participant count = 10)
    657.28 ( 1.287 )
    0 ( 0 )
        Doxorubicin (Participant count = 13)
    0 ( 0 )
    740.58 ( 1.229 )
    Notes
    [18] - Doxorubicin (Participant count = 10)
    [19] - Doxorubicin (Participant count = 13)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose (Day 1 of Cycle 1) of study drug until 30 days after the last dose of study drug.
    Adverse event reporting additional description
    Safety population consisted of all subjects who received any amount of study drug. The safety population was used for all safety analyses (incidence of adverse events (AEs) - serious and non-serious, vital signs, laboratory, physical examination, ECG, LVEF, concomitant medications and medication exposure).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Doxorubicin
    Reporting group description
    		 Subjects received doxorubicin (75 mg/m2) either by bolus injection (no less than 5 minutes) or by continuous intravenous (IV) infusion over 6-96 hours on Day 1 of every 21-day cycle; doxorubicin was not administered after 6 cycles of treatment.

    Reporting group title
    TH-302 + Doxorubicin
    Reporting group description
    		 Subjects received TH-302 (300 mg/m2) by IV infusion over 30-60 minutes on Days 1 and 8 of a 21-day cycle. Combination arm overall data were mentioned for the number of subjects affected, AEs (SAE and NSAE) and fatalities of all occurrences. AEs (SAE and NSAE) occurrences and fatalities causally related to treatment data were presented only for TH-302 treatment.

    Serious adverse events
    		 Doxorubicin TH-302 + Doxorubicin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    99 / 323 (30.65%)
    145 / 317 (45.74%)
         number of deaths (all causes)
    3
    8
         number of deaths resulting from adverse events
    1
    5
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant Pleural effusion
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour rupture
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    5 / 323 (1.55%)
    3 / 317 (0.95%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 323 (0.31%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 323 (0.62%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis necrotising
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cytoreductive surgery
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leg amputation
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial lung resection
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sarcoma excision
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour excision
         subjects affected / exposed
    2 / 323 (0.62%)
    2 / 317 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 323 (0.31%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Extravasation
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 323 (0.93%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 323 (0.31%)
    2 / 317 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 323 (0.62%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    3 / 323 (0.93%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    7 / 323 (2.17%)
    7 / 317 (2.21%)
         occurrences causally related to treatment / all
    3 / 9
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic Inflammatory Response Syndrome
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 323 (0.31%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval disorder
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 323 (0.31%)
    3 / 317 (0.95%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    3 / 323 (0.93%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 323 (0.93%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 323 (0.31%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    3 / 323 (0.93%)
    5 / 317 (1.58%)
         occurrences causally related to treatment / all
    0 / 4
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    9 / 323 (2.79%)
    15 / 317 (4.73%)
         occurrences causally related to treatment / all
    1 / 9
    2 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Confusional state
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 323 (0.31%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet Count Decreased
         subjects affected / exposed
    1 / 323 (0.31%)
    2 / 317 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ilium fracture
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 323 (0.31%)
    2 / 317 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Amputation stump pain
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    4 / 323 (1.24%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    10 / 323 (3.10%)
    19 / 317 (5.99%)
         occurrences causally related to treatment / all
    10 / 12
    17 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    1 / 323 (0.31%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    27 / 323 (8.36%)
    56 / 317 (17.67%)
         occurrences causally related to treatment / all
    30 / 30
    68 / 71
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 323 (0.00%)
    3 / 317 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    7 / 323 (2.17%)
    8 / 317 (2.52%)
         occurrences causally related to treatment / all
    7 / 7
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 323 (0.62%)
    13 / 317 (4.10%)
         occurrences causally related to treatment / all
    2 / 2
    13 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 323 (0.62%)
    13 / 317 (4.10%)
         occurrences causally related to treatment / all
    2 / 2
    16 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    7 / 323 (2.17%)
    2 / 317 (0.63%)
         occurrences causally related to treatment / all
    1 / 8
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 323 (0.00%)
    2 / 317 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 323 (0.31%)
    2 / 317 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 323 (0.31%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised intraabdominal fluid collection
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    5 / 323 (1.55%)
    2 / 317 (0.63%)
         occurrences causally related to treatment / all
    5 / 5
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal fissure
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    5 / 323 (1.55%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 323 (0.31%)
    9 / 317 (2.84%)
         occurrences causally related to treatment / all
    1 / 1
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 323 (0.00%)
    4 / 317 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic pain
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 323 (0.00%)
    2 / 317 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck Pain
         subjects affected / exposed
    1 / 323 (0.31%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    2 / 323 (0.62%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal wall abscess
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    2 / 323 (0.62%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 323 (0.31%)
    6 / 317 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 323 (0.31%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site infection
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oropharyngeal candidiasis
         subjects affected / exposed
    1 / 323 (0.31%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 323 (1.55%)
    8 / 317 (2.52%)
         occurrences causally related to treatment / all
    0 / 5
    6 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 323 (0.00%)
    2 / 317 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 323 (0.93%)
    7 / 317 (2.21%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    2 / 3
    Septic shock
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 323 (0.31%)
    2 / 317 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    3 / 323 (0.93%)
    5 / 317 (1.58%)
         occurrences causally related to treatment / all
    1 / 3
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 323 (0.00%)
    2 / 317 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 323 (0.93%)
    5 / 317 (1.58%)
         occurrences causally related to treatment / all
    3 / 3
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 323 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic Acidosis
         subjects affected / exposed
    1 / 323 (0.31%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Doxorubicin TH-302 + Doxorubicin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    307 / 323 (95.05%)
    312 / 317 (98.42%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    10 / 323 (3.10%)
    17 / 317 (5.36%)
         occurrences all number
    11
    18
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    34 / 323 (10.53%)
    40 / 317 (12.62%)
         occurrences all number
    43
    61
    Chills
         subjects affected / exposed
    10 / 323 (3.10%)
    18 / 317 (5.68%)
         occurrences all number
    10
    20
    Fatigue
         subjects affected / exposed
    162 / 323 (50.15%)
    190 / 317 (59.94%)
         occurrences all number
    187
    226
    Oedema peripheral
         subjects affected / exposed
    36 / 323 (11.15%)
    38 / 317 (11.99%)
         occurrences all number
    44
    45
    Pyrexia
         subjects affected / exposed
    41 / 323 (12.69%)
    71 / 317 (22.40%)
         occurrences all number
    51
    107
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    43 / 323 (13.31%)
    59 / 317 (18.61%)
         occurrences all number
    47
    72
    Dyspnoea
         subjects affected / exposed
    34 / 323 (10.53%)
    66 / 317 (20.82%)
         occurrences all number
    35
    83
    Oropharyngeal pain
         subjects affected / exposed
    19 / 323 (5.88%)
    28 / 317 (8.83%)
         occurrences all number
    19
    32
    Pulmonary embolism
         subjects affected / exposed
    17 / 323 (5.26%)
    21 / 317 (6.62%)
         occurrences all number
    18
    21
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    15 / 323 (4.64%)
    30 / 317 (9.46%)
         occurrences all number
    15
    32
    Depression
         subjects affected / exposed
    15 / 323 (4.64%)
    30 / 317 (9.46%)
         occurrences all number
    15
    31
    Insomnia
         subjects affected / exposed
    37 / 323 (11.46%)
    23 / 317 (7.26%)
         occurrences all number
    37
    24
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    6 / 323 (1.86%)
    18 / 317 (5.68%)
         occurrences all number
    6
    20
    Ejection fraction decreased
         subjects affected / exposed
    31 / 323 (9.60%)
    39 / 317 (12.30%)
         occurrences all number
    31
    40
    Lymphocyte count decreased
         subjects affected / exposed
    13 / 323 (4.02%)
    19 / 317 (5.99%)
         occurrences all number
    22
    32
    Neutrophil count decreased
         subjects affected / exposed
    44 / 323 (13.62%)
    34 / 317 (10.73%)
         occurrences all number
    74
    45
    Platelet count decreased
         subjects affected / exposed
    20 / 323 (6.19%)
    35 / 317 (11.04%)
         occurrences all number
    35
    64
    Weight decreased
         subjects affected / exposed
    18 / 323 (5.57%)
    44 / 317 (13.88%)
         occurrences all number
    18
    44
    White blood cell count decreased
         subjects affected / exposed
    39 / 323 (12.07%)
    45 / 317 (14.20%)
         occurrences all number
    77
    77
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    20 / 323 (6.19%)
    35 / 317 (11.04%)
         occurrences all number
    22
    47
    Dysgeusia
         subjects affected / exposed
    41 / 323 (12.69%)
    70 / 317 (22.08%)
         occurrences all number
    44
    75
    Headache
         subjects affected / exposed
    36 / 323 (11.15%)
    52 / 317 (16.40%)
         occurrences all number
    39
    55
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    104 / 323 (32.20%)
    189 / 317 (59.62%)
         occurrences all number
    130
    287
    Febrile neutropenia
         subjects affected / exposed
    34 / 323 (10.53%)
    57 / 317 (17.98%)
         occurrences all number
    37
    75
    Leukopenia
         subjects affected / exposed
    28 / 323 (8.67%)
    30 / 317 (9.46%)
         occurrences all number
    56
    69
    Neutropenia
         subjects affected / exposed
    96 / 323 (29.72%)
    60 / 317 (18.93%)
         occurrences all number
    171
    118
    Thrombocytopenia
         subjects affected / exposed
    19 / 323 (5.88%)
    72 / 317 (22.71%)
         occurrences all number
    22
    156
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    13 / 323 (4.02%)
    16 / 317 (5.05%)
         occurrences all number
    13
    16
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    31 / 323 (9.60%)
    37 / 317 (11.67%)
         occurrences all number
    32
    41
    Abdominal pain upper
         subjects affected / exposed
    6 / 323 (1.86%)
    16 / 317 (5.05%)
         occurrences all number
    6
    16
    Constipation
         subjects affected / exposed
    89 / 323 (27.55%)
    134 / 317 (42.27%)
         occurrences all number
    99
    162
    Diarrhoea
         subjects affected / exposed
    68 / 323 (21.05%)
    96 / 317 (30.28%)
         occurrences all number
    86
    144
    Dry mouth
         subjects affected / exposed
    12 / 323 (3.72%)
    33 / 317 (10.41%)
         occurrences all number
    13
    34
    Dyspepsia
         subjects affected / exposed
    39 / 323 (12.07%)
    37 / 317 (11.67%)
         occurrences all number
    45
    43
    Dysphagia
         subjects affected / exposed
    6 / 323 (1.86%)
    20 / 317 (6.31%)
         occurrences all number
    6
    21
    Gastrooesophageal reflux disease
         subjects affected / exposed
    17 / 323 (5.26%)
    24 / 317 (7.57%)
         occurrences all number
    17
    24
    Haemorrhoids
         subjects affected / exposed
    11 / 323 (3.41%)
    43 / 317 (13.56%)
         occurrences all number
    11
    49
    Nausea
         subjects affected / exposed
    180 / 323 (55.73%)
    210 / 317 (66.25%)
         occurrences all number
    266
    300
    Proctalgia
         subjects affected / exposed
    2 / 323 (0.62%)
    22 / 317 (6.94%)
         occurrences all number
    2
    23
    Stomatitis
         subjects affected / exposed
    106 / 323 (32.82%)
    162 / 317 (51.10%)
         occurrences all number
    149
    232
    Vomiting
         subjects affected / exposed
    62 / 323 (19.20%)
    101 / 317 (31.86%)
         occurrences all number
    82
    136
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    138 / 323 (42.72%)
    153 / 317 (48.26%)
         occurrences all number
    138
    153
    Dry skin
         subjects affected / exposed
    17 / 323 (5.26%)
    34 / 317 (10.73%)
         occurrences all number
    18
    43
    Erythema
         subjects affected / exposed
    6 / 323 (1.86%)
    25 / 317 (7.89%)
         occurrences all number
    6
    28
    Rash
         subjects affected / exposed
    3 / 323 (0.93%)
    19 / 317 (5.99%)
         occurrences all number
    3
    25
    Rash erythematous
         subjects affected / exposed
    4 / 323 (1.24%)
    23 / 317 (7.26%)
         occurrences all number
    4
    31
    Rash maculo-papular
         subjects affected / exposed
    4 / 323 (1.24%)
    27 / 317 (8.52%)
         occurrences all number
    4
    38
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 323 (0.31%)
    35 / 317 (11.04%)
         occurrences all number
    1
    38
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    2 / 323 (0.62%)
    41 / 317 (12.93%)
         occurrences all number
    2
    48
    Pruritus
         subjects affected / exposed
    1 / 323 (0.31%)
    23 / 317 (7.26%)
         occurrences all number
    2
    29
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    9 / 323 (2.79%)
    16 / 317 (5.05%)
         occurrences all number
    11
    18
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    18 / 323 (5.57%)
    40 / 317 (12.62%)
         occurrences all number
    21
    42
    Back pain
         subjects affected / exposed
    26 / 323 (8.05%)
    39 / 317 (12.30%)
         occurrences all number
    27
    44
    Bone pain
         subjects affected / exposed
    12 / 323 (3.72%)
    31 / 317 (9.78%)
         occurrences all number
    12
    36
    Myalgia
         subjects affected / exposed
    12 / 323 (3.72%)
    19 / 317 (5.99%)
         occurrences all number
    13
    22
    Pain in extremity
         subjects affected / exposed
    22 / 323 (6.81%)
    32 / 317 (10.09%)
         occurrences all number
    26
    41
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    4 / 323 (1.24%)
    18 / 317 (5.68%)
         occurrences all number
    4
    20
    Oral candidiasis
         subjects affected / exposed
    5 / 323 (1.55%)
    16 / 317 (5.05%)
         occurrences all number
    5
    20
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 323 (2.48%)
    20 / 317 (6.31%)
         occurrences all number
    9
    26
    Urinary tract infection
         subjects affected / exposed
    26 / 323 (8.05%)
    47 / 317 (14.83%)
         occurrences all number
    30
    62
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    82 / 323 (25.39%)
    113 / 317 (35.65%)
         occurrences all number
    93
    128
    Dehydration
         subjects affected / exposed
    13 / 323 (4.02%)
    28 / 317 (8.83%)
         occurrences all number
    17
    37
    Hypoalbuminaemia
         subjects affected / exposed
    10 / 323 (3.10%)
    18 / 317 (5.68%)
         occurrences all number
    13
    22
    Hypokalaemia
         subjects affected / exposed
    20 / 323 (6.19%)
    35 / 317 (11.04%)
         occurrences all number
    21
    44

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jun 2012
    Amendment 1: 1. Provide greater clarification of the eligibility criteria including: - The inclusion of subjects with Gilbert's syndrome who had an associated elevated bilirubin - The inclusion of other STSs for which doxorubicin was an appropriate first-time therapy - The inclusion of subjects who were not transfusion dependent if baseline hematological laboratory data met eligibility - The modification of the restriction of prior therapies to only those that were related to the subject's STS - The inclusion of subjects who received low dose non-systemic doxorubicin and - The exclusion of doxorubicin-limiting congestive heart failure 2. Clarified that complete resection of all sites of disease was a reason for treatment discontinuation 3. Provided greater detail on the analyses of PFS 4. Eliminated event-free survival as a secondary objective 5. Re-categorized the secondary efficacy objectives and endpoints into secondary and tertiary objectives and endpoints 6. Expanded the doxorubicin continuous IV infusion to 6.96 hours 7. Clarified the treatment options following tumor resection  8. Correctly specified the statistical test for comparing rates across treatment arms 9. Provided guidance in the event of extravasation 10. Included minor administrative and protocol changes.
    20 Dec 2012
    Amendment 2: 1. Added pre-H-302 dose and post-TH-302 dose ECG assessments of the QTc interval 2. Allowed for an increase of the study sample size if over 10 subjects discontinued from study and withdrew consent for future follow-up, including survival 3. Added collection of EQ-5D-5L to collect data on quality of life data and health state utilities 4. Included minor administrative and protocol changes
    22 Apr 2013
    Amendment 3: 1. Increased the sample size from 450 subjects to 620 subjects 2. Removed the PFS interim futility analysis 3. Adjusted the timing of the OS interim analysis 4. Clarified one of the exclusion criteria 5. Included minor administrative and protocol changes

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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